Bcl-2 inhibitors for use in the treatment of a bcl-2 mediated cancer carrying the gly101val mutation

Abstract

The invention relates to a Bcl-2 inhibitor for use in the treatment of a Bcl-2 mediated cancer carrying at least 1, 2, 3, 4, 5 or all of the following mutations: (i) Gly101Val; (ii) Asp103Tyr; (iii) Asp103Val; (iv) Asp103Glu; (v) Arg129Leu and (vi) Ala113Gly; wherein the Bcl-2 inhibitor is N-(4-hydroxyphenyl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-N-phenyl-5,6,7,8-tetrahydro-1-indolizine carboxamide (Compound A) or 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-iH-pyrrole-3-carboxamide (Compound B), or a pharmaceutically acceptable salt thereof.

1 - 22 . (canceled) 
     
     
         23 . A method of treating a Bcl-2 mediated cancer carrying at least 1, 2, 3, 4, 5 or all of the following mutations: (i) Gly101Val; (ii) Asp103Tyr; (iii) Asp103Val; (iv) Asp103Glu; (v) Arg129Leu and (vi) Ala113Gly; in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of of a Bcl-2 inhibitor selected from the group consisting of N-(4-hydroxyphenyl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-N-phenyl-5,6,7,8-tetrahydro-1-indolizine carboxamide (Compound A) and 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (Compound B), and pharmaceutically acceptable salts thereof, wherein the Bcl-2 inhibitor is administered alone or in combination with one or more pharmaceutically acceptable excipients. 
     
     
         24 . The method according to  claim 23 , wherein the Bcl-2 mediated cancer carries the Gly101Val mutation. 
     
     
         25 . The method according to  claim 23 , wherein the Bcl-2 mediated cancer carries the Asp103Tyr mutation. 
     
     
         26 . The method according to  claim 23 , wherein the Bcl-2 mediated cancer carries the Asp103Val mutation. 
     
     
         27 . The method according to  claim 23 , wherein the Bcl-2 mediated cancer carries the Asp103Glu mutation. 
     
     
         28 . The method according  claim 23 , wherein the Bcl-2 mediated cancer is chronic lymphocytic leukemia (CLL). 
     
     
         29 . The method according to  claim 23 , wherein the Compound A is in the form of a hydrochloride salt. 
     
     
         30 . The method according to  claim 23 , wherein the Compound B is in the form of a hydrogen sulfate salt. 
     
     
         31 . The method according to  claim 23 , wherein the Compound B is in the form of a hydrochloride salt. 
     
     
         32 . The method according to  claim 23 , wherein Compound B is administered intravenously. 
     
     
         33 . A method for sensitizing a patient having a Bcl-2 mediated cancer carrying at least 1, 2, 3, 4, 5 or all of the following mutations: (i) Gly101Val; (ii) Asp103Tyr; (iii) Asp103Val; (iv) Asp103Glu; (v) Arg129Leu and (vi) Ala113Gly;
 who is (a) refractory to at least one anti-cancer agent, or (b) in relapse after treatment with an anti-cancer agent, or both (a) and (b), wherein the method comprises administering a therapeutically effective amount of a Bcl-2 inhibitor selected from the group consisting of N-(4-hydroxyphenyl)-3-{(6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-N-phenyl-5,6,7,8-tetrahydro-1-indolizine carboxamide (Compound A) and 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (Compound B), and pharmaceutically acceptable salts thereof, to said patient.   
     
     
         34 . A method for sensitizing a patient having a Bcl-2 mediated cancer carrying the Gly101Val mutation who is (i) refractory to at least one anti-cancer agent, or (ii) in relapse after treatment with an anti-cancer agent, or both (i) and (ii), wherein the method comprises administering a therapeutically effective amount of a Bcl-2 inhibitor selected from the group consisting of N-(4-hydroxyphenyl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-N-phenyl-5,6,7,8-tetrahydro-1-indolizine carboxamide (Compound A) and 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (Compound B), and pharmaceutically acceptable salts thereof, to said patient. 
     
     
         35 . The method according to  claim 33 , wherein the anti-cancer agent is a targeted therapy. 
     
     
         36 . The method according to  claim 35 , wherein the cancer is chronic lymphocytic leukemia (CLL). 
     
     
         37 . The method according to  claim 35 , wherein the targeted therapy is venetoclax (ABT-199). 
     
     
         38 . The method according to  claim 34 , wherein the anti-cancer agent is a targeted therapy. 
     
     
         39 . The method according to  claim 38 , wherein the cancer is chronic lymphocytic leukemia (CLL). 
     
     
         40 . The method according to  claim 38 , wherein the targeted therapy is venetoclax (ABT-199). 
     
     
         41 . A method of treating a Bcl-2 mediated cancer in a patient, comprising the steps of:
 (a) obtaining a biological sample from said patient and detecting whether the biological sample comprises at least 1, 2, 3, 4, 5 or all of the following mutations: (i) Gly101Val; (ii) Asp103Tyr, (iii) Asp103Val; (iv) Asp103Glu; (v) Arg129Leu and (vi) Ala113Gly;   (b) identifying said patients as having reduced likelihood of response to venetoclax;   (c) administering a therapeutically effective amount of a Bcl-2 inhibitor selected from the group consisting of N-(4-hydroxyphenyl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl}-N-phenyl-5,6,7,8-tetrahydro-1-indolizine carboxamide (Compound A) and 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (Compound B), and pharmaceutically acceptable salts thereof, to said patient based on the presence of the thus detected mutations.   
     
     
         42 . A method of treating a Bcl-2 mediated cancer in a patient, comprising the steps of:
 (a) obtaining a biological sample from said patient and detecting whether the biological sample comprises the Gly101Val mutation;   (b) identifying said patients as having reduced likelihood of response to venetoclax;   (c) administering a therapeutically effective amount of a Bcl-2 inhibitor selected from the group consisting of N-(4-hydroxyphenyl)-3-{6-[((3S)-3-(4-morpholinylmethyl)-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl]-1,3-benzodioxol-5-yl-N}-phenyl-5,6,7,8-tetrahydro-1-indolizine carboxamide (Compound A) and 5-(5-chloro-2-{[(3)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide (Compound B), and pharmaceutically acceptable salts thereof, to said patient based on the presence of the Gly101Val mutation.